Oncocytic Adenocarcinoma of the Stomach: Comparison with Parietal Cell Carcinoma

Oncocytic Adenocarcinoma of the Stomach: Comparison with Parietal Cell Carcinoma

Kaiyo Takubo

and Tomio Arai

Introduction

Primary adenocarcinomas of the stomach are usually divided histologically into diffuse and intestinal types [1]. However, a number of rare histologic variants have been reported, including choriocarcinoma, hepatoid carcinoma, carcinoma with lym- phoid stroma (Epstein–Barr virus-related carcinoma), Paneth cell carcinoma [2], neuroendocrine carcinoma, small cell carcinoma, gastric carcinoma with rhabdoid features [3], and parietal cell carcinoma [4]. Among them, hepatoid carcinoma and carcinoma with lymphoid stroma are described elsewhere in this volume (see the chapters by H. Ishikura and J.-M. Chong). Some of these variants have been reported to have a better or worse prognoses than the usual type of adenocarcinoma.

Parietal cell carcinoma of the stomach is very rare, with only 16 cases reported to date [5–11], and is suggested to have a better prognosis than the usual type of gastric adenocarcinoma. It consists of cells with abundant eosinophilic cytoplasm that, on ultrastructural examination, have numerous mitochondria, intracytoplasmic secre- tory canaliculi, and cytoplasmic tubulovesicles. These histologic and ultrastructural features are considered to be very similar to those of parietal cells in the normal gastric fundic mucosa [7]. The carcinomas in the 16 reported cases showed solid sheets of rather uniform or fusiform cells with only focal glandular structures [5–11].

We have reported a category different from parietal cell carcinoma, although the morphologic features are similar.

We have described 10 well- to moderately differentiated papillotubular adenocar- cinomas of the stomach with oncocytic features and compared them with the features of the 16 reported cases of parietal cell carcinoma [12]. Over the last few years we have found 4 more papillotubular adenocarcinomas with oncocytic differentiation; these differed histologically from gastric parietal cell carcinoma cells but were ultrastruc- turally similar to them and also to normal gastric parietal cells. However, all 14 adenocarcinomas were negative on immunostaining with four different antibodies against H

-K

-ATPase.

151

1

Human Tissue Research Group, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan

2

Tokyo Metropolitan Geriatric Medical Center, Tokyo, Japan

e-mail: takubo@tmig.or.jp

Incidence of Oncocytic Adenocarcinoma Among Gastric Carcinomas in Terms of Patient Age and Sex

In a previous article [12], we described 10 patients (9 male, 1 female) with well- to moderately differentiated tubular or papillotubular adenocarcinoma in which the car- cinoma cells had eosinophilic, finely granular cytoplasm. These cases were encoun- tered over an 8-year period (1993–2000) at the Department of Clinical Pathology, Tokyo Metropolitan Geriatric Medical Center, and accounted for 1.8% of a total of 554 gastric carcinomas encountered over this period. In the 2 years (2001–2002) since then, we have newly encountered 4 (2.5%) patients (all male) with gastric oncocytic carcinoma among 162 patients with gastric malignancy, making the overall incidence 14 (2.0%) of 716 patients.

The 14 patients ranged in age from 58 to 84 years (mean, 70.2 years). Four were in their eighties, 5 in their seventies, 4 in their sixties, and 1 in his fifties. Nine of the patients were treated by gastrectomy and the remaining 5, who were considered on the basis of endoscopy and endoscopic ultrasonography to have mucosal carcinomas without metastasis, were treated by laser ablation or endoscopic resection. On the basis of WHO staging, 10 patients (including the 5 treated by laser ablation or endo- scopic resection) were in stage IA, 2 were in stage IB, and 2 were in stage IIIA. The 10 stage IA carcinomas were macroscopically type 0-IIa, superficial elevated type (Fig.

1 ) [13].

Histopathologic Findings

The intramucosal and deeply invasive portions of the 14 carcinomas were always well- to moderately differentiated tubular or papillotubular adenocarcinoma without poorly differentiated or undifferentiated areas (Fig. 2). The carcinoma cells in the mucosal components and superficially invasive portions had finely granular eosinophilic cytoplasm and round nuclei. However, in the deeply invasive portions, the carcinoma cells contained less eosinophilic cytoplasm. The carcinoma cell cyto- plasm was relatively abundant. In the mucosa, the cell nuclei occasionally had very prominent nucleoli and intranuclear invaginations of cytoplasm. Cells with irregular, large nuclei with prominent nucleoli were also frequent, especially in the area near the lamina muscularis mucosae (Fig. 3). In the invasive portions, the nuclei had relatively small nucleoli. Therefore, oncocytic features were typically present in the mucosal components with invasive carcinoma or intramucosal carcinoma. Oncocytes have been described as cells with abundant, finely granular eosinophilic cytoplasm that are normally found in the salivary glands [14] and parathyroid glands [14].

Benign oncocytic tumors may arise in the salivary glands, gastrointestinal tract [15], lung, kidney, and other sites. Papotti et al. [15] have suggested the existence of a gastric neoplasm that is rich in mitochondria.

Malignant oncocytomas, although rare, are known to occur occasionally in the sali-

vary glands, thorax, breast, pancreas, and other sites. Both neoplastic and nonneo-

plastic oncocytes exhibit solid and papillary-tubular architectural patterns and have

oxyphilic granular cytoplasm because of the presence of numerous mitochondria in

their cytoplasm. These histologic and ultrastructural features are similar to those of the carcinomas in the present study. Our carcinomas can therefore be termed onco- cytic carcinomas, or carcinomas showing oncocytic differentiation.

Mucin and Lectin Histochemistry and Immunohistochemistry

A few cells in some of the carcinomas showed cytoplasmic periodic acid-Schiff (PAS) and/or alcian blue positivity but were negative for lectin by the concavalin A (Con A) method. The cells were generally also negative for Muc-2, with only a few cells in the mucosal layer staining positive, and were negative for HGM .

The normal parietal cells and the carcinoma cells near the lamina muscularis mucosae showed the most strongly positive staining with the antimitochondrial anti- body MAB 1273. Chief cells and metaplastic absorptive cells were less strongly posi- tive than carcinoma cells, whereas the gastric surface epithelium, pyloric glands and goblet cells showed much weaker staining (Fig. 4).

The normal gastric parietal cells showed strongly positive staining with all four antiparietal cell antibodies. The gastric pyloric glands, the metaplastic mucosa, and the carcinoma cells did not stain with any of the four antibodies. A micrograph of a section stained using anti-H

-K

-ATPase-subunit (N-terminal sequence) is shown in Fig. 5.

Ultrastructural Study

The present carcinoma cells formed tubules with microvilli on their luminal surfaces, and there were junctional complexes and desmosomes between cells. Intra- cytoplasmic and intercellular lumina, with many microvilli, were also seen occasion- ally. The nuclei had prominent and irregular nucleoli. The cytoplasm contained numerous mitochondria near the lamina muscularis mucosae (Fig. 6), while fewer mitochondria were observed in the cells in or near the mucosal surface (Fig. 7). This result was consistent with the findings of immunohistochemical mitochondrial staining.

Normal gastric parietal cells have H

-K

-ATPase as a proton pump. It is located mainly near free cellular membranes and the membranes of intracytoplasmic canali- culi. The normal gastric parietal cells were stained very strongly positive with four different antiparietal cell antibodies, whereas the carcinoma cells were negative. If the presence of H

-K

-ATPase is one of the most important features of parietal cells, then our carcinomas cannot be said to have shown parietal cell differentiation, and therefore cannot be diagnosed as parietal cell carcinomas. Amorphous secretory material was present in some intracytoplasmic canaliculi (Fig. 8), but well-developed tubulovesicles were rarely observed. If present, tubulovesicles were adjacent to cell- surface membranes.

It has been reported that intracytoplasmic canaliculi are ultrastructural markers of

glandular tissue and adenocarcinoma, including gastric adenocarcinoma of the usual

Fig. 6. Carcinoma cells near the lamina muscularis mucosae. The tumor cells have microvilli at their luminal surfaces, and there are junctional complexes with desmosomes between cells.

The cells have numerous mitochondria. The nucleus has prominent and irregular nucleoli. An intercellular lumen is seen and is associ- ated with microvilli (left top).

There is amorphous secretory material in the lumen. ¥4800

Fig. 7. The carcinoma cells in the mucosal surface layer. The tumor cells have fewer mito- chondria than those near the lamina muscularis mucosae.

The nucleus also has irregu- lar nucleoli. An intercellular lumen is seen and is associ- ated with microvilli (right top). There is amorphous secretory material in the lumen. ¥3600

Fig. 8. An intracytoplasmic lumen is seen and is associ- ated with long microvilli.

There is amorphous secretory material in the lumen.

Tubulovesicles are not

observed around the intracy-

toplasmic lumen. ¥19 000

type, but they are rare in adenomas and normal secretory cells [16]. However, the intracytoplasmic lumina seen in parietal cell carcinomas differ from those seen in gastric adenocarcinomas of the usual type and carcinomas arising at other sites [16].

The intracytoplasmic canaliculi of usual-type gastric adenocarcinomas contain electron-dense homogeneous granular material, and there is no communication between the canaliculi and the extracellular space [16]. In the carcinomas we studied, it was difficult to determine whether communication existed between the canaliculi and the extracellular space. The presence of intracytoplasmic canaliculi with microvilli, many mitochondria, and tubulovesicles, but with an absence of mucin secretory granules, is a characteristic feature of parietal cell differentiation [7,16].

Differences between Parietal Cell Carcinoma and Oncocytic Adenocarcinoma

It has been said that parietal cell carcinoma of the stomach is very rare, and indeed only 16 cases have been reported previously; however, our findings suggest that our variant may not be so rare in Japan. Previously reported cases of gastric parietal cell carcinoma were diagnosed on the basis of staining using hematoxylin and eosin (H&E), phosphotungstic acid-hematoxylin (PTAH), and Klüver–Barrera Luxol Fast Blue, and also by electron microscopy [5–11]. The PTAH and Luxol Fast Blue methods are known to stain parietal cells and other cells rich in mitochondria, including oncocytes [7].

The previously reported carcinomas diagnosed as gastric parietal cell carcinoma have been variously described as showing a diffuse, poorly differentiated, or solid pattern with a rare tubular pattern [5–8,10], a leiomyosarcoma- or leiomyoblastoma- like pattern [9,11], or spindle [11] cells. Therefore, on the basis of histology, our car- cinomas may be in a different category from these parietal cell carcinomas. Parietal cell carcinoma has been reported to be generally negative on PAS and alcian blue staining, and electron microscopy has not revealed cytoplasmic mucin granules [5,6,10,11]. We observed no Con A- or HGM-positive cells in our carcinomas, and Muc-2-positive cells were very infrequent. Thus, our carcinomas did not show the mucin phenotype of normal gastric mucosa, and the intestinal mucin phenotype was observed in only a few of the cells.

The carcinomas reported previously as parietal cell carcinomas often had intracy- toplasmic canaliculi and multiple mitochondria, but tubulovesicles were said to be either absent or infrequent. Capella et al. [7] described a discrete number of tubulovesicles, intermingled with mitochondria, in a small group of gastric parietal cell carcinomas.

Intracytoplasmic lumina were occasionally observed in our carcinomas, but tubulovesicles were infrequent. Intracytoplasmic lumina have been observed in onco- cytic neoplasms of the pancreas. Therefore, as with the immunohistochemical find- ings, the ultrastructural findings of our study do not allow a diagnosis of parietal cell carcinoma or carcinoma with parietal cell differentiation, but only one of oncocytic adenocarcinoma or carcinoma with oncocytic differentiation.

We believe that the diagnosis of parietal cell carcinoma of the stomach should be

based not only on histologic and ultrastructural findings but also on immunohisto-

chemical staining using antiparietal cell antibodies. The previously reported parietal cell carcinomas could not be tested with these antibodies; they showed wide varia- tions in their histological and ultrastructural features, and it seems doubtful that all of them showed true parietal differentiation.

Prognosis of Parietal Cell Carcinoma and Oncocytic Adenocarcinoma

All 16 parietal cell carcinomas reported to date were said to have a favorable outcome [7]. Our present 14 carcinomas were at mainly very early stages and it was thus diffi- cult to determine whether their prognosis would have been significantly different from that of gastric adenocarcinoma of the usual type. Further investigation of the prognosis of this group of carcinomas is needed.

Conclusion

The carcinomas we have described here may constitute a different category from those reported previously as parietal cell carcinoma, but it would be of interest to stain the latter carcinomas using antiparietal cell antibodies, now that such antibodies have become available. Similar to parietal cell carcinoma, oncocytic adenocarcinoma of the stomach is an uncommon variant of gastric cancer that occurs particularly in older patients, and most cases were detected in the early stages. More needs to be learned about the clinicopathologic features of this subtype, and especially the prognosis.

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Fig. 1. Macroscopic features of an early-stage oncocytic adenocarcinoma. A slightly elevated intramucosal tumor is evident in the posterior wall of the stomach, and shows only a small focus of submucosal invasion

Fig. 2. Intramucosal compo- nents of oncocytic adenocar- cinoma of the stomach. The carcinoma shows a tubular pattern and the cells have markedly eosinophilic cyto- plasm. ¥100

Color Plates

Fig. 3. Intramucosal oncocytic adenocarcinoma near the lamina muscularis mucosae. The carcinoma cells have prominently eosinophilic, finely granular cytoplasm and atypical nuclei with very prominent nucleoli. ¥400

Fig. 4. The carcinoma cells near the lamina muscularis mucosae are stained strongly positive with antimitochon- drial antibody MAB 1273, but the pyloric glands (right bottom) react much more weakly. ¥200

Fig. 5. Nonneoplastic pari- etal cells stain positively with anti-H

-K

-ATPase-subunit (N-terminal sequence) anti- body (right); carcinoma cells are negative (left). Normal gastric parietal cells were stained strongly positive with all four different anti-H

-K

- ATPase-subunit (N-terminal and C-terminal) polyclonal antibodies used, whereas car- cinoma cells were unstained with any of the antibodies.

¥100